2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Abstract

A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher's; or Fabry's disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

What is claimed is: 
     
       1. A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is a phenyl group optionally substituted with one or more substituents selected from halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR 30 , —SR 30 , —N(R 31 ) 2 , Ar 1 , —V o —OR 30 , —V o —N(R 31 ) 2 , —V o —Ar 1 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —O—[CH 2 ] p —O—, —S—[CH 2 ] p —S— or —[CH 2 ] q —;
 Ar 1  is a phenyl group each optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; and 
 each R 30  is independently 
 i) hydrogen; 
 ii) a phenyl group optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; or 
 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; and 
 each R 31  is independently R 30 , or —N(R 31 ) 2  is an optionally substituted non-aromatic heterocyclic group; 
 
         —N(R 2 R 3 ) is a pyrrolidinyl group optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, —OR 40 , —O(haloalkyl), —SR 40 , —NO 2 , —CN, —N(R 41 ) 2 , —NR 41 C(O)R 40 , —NR 41 C(O)OR 42 , —N(R 41 )C(O)N(R 41 ) 2 , —C(O)R 40 , —C(S)R 40 , —C(O)OR 40 , —OC(O)R 40 , —C(O)N(R 41 ) 2 , —S(O) 2 R 40 , —SO 2 N(R 41 ) 2 , —S(O)R 42 , —SO 3 R 40 , Ar 2 , V 2 —Ar 2 , —V 2 —OR 40 , —V 2 —O(haloalkyl), —V 2 —SR 40 , —V 2 —NO 2 , —V 2 —CN, —V 2 —N(R 41 ) 2 , —V 2 —NR 41 C(O)R 40 , —V 2 —NR 41 CO 2 R 42 , —V 2 —N(R 41 )C(O)N(R 41 ) 2 , —V 2 —C(O)R 40 , —V 2 —C(S)R 40 , —V 2 —CO 2 R 40 , —V 2 —OC(O)R 40 , —V 2 —C(O)N(R 41 ) 2 —, —V 2 —S(O) 2 R 40 , —V 2 —SO 2 N(R 41 ) 2 , —V 2 —S(O)R 42 , —V 2 —SO 3 R 40 , —O—V 2 —Ar 2  or —S—V 2 —Ar 2 ;
 each V 2  is independently a C1-C4 alkylene group; 
 Ar 2  is an aryl group each optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; and 
 each R 40  is independently 
 i) hydrogen; 
 ii) an aryl group optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; or 
 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; and 
 each R 41  is independently R 40 , —CO 2 R 40 , —SO 2 R 40  or —C(O)R 40 ; or 
 
         —N(R 41 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group; and each R 42  is independently:
 i) an aryl group optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; or 
 ii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkyl; 
 
         R 4  is an aliphatic group or an aryl group optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, Ar 3 , Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —NCS, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —NR 51 C(O)OR 52 , —N(R 51 )C(O)N(R 51 ) 2 , —C(O)R 50 , —C(S)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —S(O) 2 R 50 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 50 , —NR 51 SO 2 N(R 51 ) 2 , —NR 51 SO 2 R 52 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —NR 51 CO 2 R 52 , —V 4 —N(R 51 )C(O)N(R 51 ) 2 , —V 4 —C(O)R 50 , —V 4 —C(S)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —V 4 —S(O) 2 R 50 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 50 , —V 4 —NR 51 SO 2 N(R 51 ) 2 , —V 4 —NR 51 SO 2 R 52 , —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(S)—V 4 —N(R 51 ) 2 , —C(S)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —S(O) 2 —V 4 —N(R 51 ) 2 , —S(O) 2 —V 4 —Ar 3 , —SO 2 N(R 51 )—V 5 —N(R 51 ) 2 , —SO 2 N(R 51 )—V 4 —Ar 3 , —S(O)—V 4 —N(R 51 ) 2 , —S(O)—V 4 —Ar 3 , —S(O) 2 —O—V 5 —N(R 51 ) 2 , —S(O) 2 —O—V 4 —Ar 3 , —NR 51 SO 2 —V 4 —N(R 51 ) 2 , —NR 51 SO 2 —V 4 —Ar 3 , —O—[CH 2 ] p′ —O—, —S—[CH 2 ] p′ —S—, or —[CH 2 ] q′ —;
 each V 4  is independently a C1-C10 alkylene group; 
 each V 5  is independently a C2-C10 alkylene group; 
 each Ar 3  is independently an aryl group each optionally substituted with one or more substituents selected from halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; and 
 each R 50  is independently 
 i) hydrogen; 
 ii) an aryl group optionally substituted with one or more substituents selected from halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; or 
 iii) an alkyl group optionally substituted with one or more substituents selected from halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; and 
 each R 51  is independently R 50 , —CO 2 R 50 , —SO 2 R 50  or —C(O)R 50 ; or 
 
         —N(R 51 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group; and each R 52  is independently:
 i) an aryl group optionally substituted with one or two substituents selected from halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; or 
 ii) an alkyl group optionally substituted with one or more substituents selected from halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl or haloalkyl; and 
 each p′ is 1, 2, 3 or 4; and 
 each q′ is 3, 4, 5 or 6; and 
 
         R 7  is —H or C1-C6 alkyl. 
       
     
     
       2. The compound of  claim 1 , wherein —N(R 2 R 3 ) is a pyrrolidinyl group optionally substituted with one or more substituents selected from halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino or C1-C5 dialkylamino. 
     
     
       3. The compound of  claim 2 , represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 8  is —H, or an aryl or C1-C6 alkyl group each optionally and independently substituted with one or more substituents selected from halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —C(O)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— or —[CH 2 ] q′ —; and 
         k is 0, 1, 2, 3, 4, 5 or 6. 
       
     
     
       4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       5. A method of treating a subject having type 2 diabetes, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       6. A method of treating a subject having renal hypertrophy or hyperplasia associated with diabetic nephropathy, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       7. A method of decreasing plasma TNF-α in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       8. A method of lowering blood glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       9. A method of decreasing glycated hemoglobin levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       10. A method of inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       11. A method of treating a subject with Tay-Sachs, Gaucher's or Fabry's disease, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound of  claim 1 , wherein the compound is a (1R,2R) stereoisomer. 
     
     
       13. The compound of  claim 2 , wherein R 7  is —H, and R 4  is an optionally substituted aryl or arylalkyl group. 
     
     
       14. The compound of  claim 13 , wherein R 4  is an aryl or arylalkyl group each optionally and independently substituted with one or more substituents selected from halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —C(O)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— or —[CH 2 ] q′ —, wherein arylalkyl includes straight and branched saturated chains containing one to six carbon atoms. 
     
     
       15. The compound of  claim 3 , wherein R 8  is selected from: 
       
         
           
           
               
               
           
         
         wherein:
 each of rings A-Z5 is optionally substituted. 
 
       
     
     
       16. The compound of  claim 15 , wherein —N(R 2 R 3 ) is an unsubstituted pyrrolidinyl group. 
     
     
       17. The compound of  claim 16 , wherein each of rings A-Z5 is optionally substituted with one or more substituents selected from halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH 2 ] p —O— or —[CH 2 ] q —. 
     
     
       18. The compound of  claim 17 , wherein:
 —N(R 2 R 3 ) is pyrrolidinyl; and 
 the phenyl group represented by R 1  is optionally substituted with one or more substituents selected from —OH, —OCH 3 , —OC 2 H 5  or —O—[CH 2 ] p —O—. 
 
     
     
       19. The compound of  claim 1 , represented by one of the following structural formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing.